CN115701423B - Preparation method of trifluoroethyl sulfide (sulfoxide) substituted benzene compounds and intermediates thereof - Google Patents
Preparation method of trifluoroethyl sulfide (sulfoxide) substituted benzene compounds and intermediates thereof Download PDFInfo
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Abstract
本发明涉及一种三氟乙基硫醚取代苯类化合物的制备方法以及在该方法中使用的中间体。所述方法包括如下步骤：步骤1)：使通式VII化合物与通式VI化合物进行缩合反应得到通式V化合物；步骤2）：使通式V化合物经历磺化反应得到通式IV化合物；步骤3）：通式IV化合物经历还原反应得到通式III化合物；步骤4）：通式III化合物经历烷基化反应得到通式II化合物。本发明还涉及一种三氟乙基亚砜取代苯类化合物的制备方法，其包括步骤：使上述通式II化合物经历氧化反应，得到通式I化合物。本发明所述的方法具有简单、高效、高收率、降低成本等优点。 The present invention relates to a method for preparing a trifluoroethyl sulfide substituted benzene compound and an intermediate used in the method. The method comprises the following steps: step 1): subjecting a compound of general formula VII to a condensation reaction with a compound of general formula VI to obtain a compound of general formula V; step 2): subjecting the compound of general formula V to a sulfonation reaction to obtain a compound of general formula IV; step 3): subjecting the compound of general formula IV to a reduction reaction to obtain a compound of general formula III; step 4): subjecting the compound of general formula III to an alkylation reaction to obtain a compound of general formula II. The present invention also relates to a method for preparing a trifluoroethyl sulfoxide substituted benzene compound, comprising the step of subjecting the compound of general formula II to an oxidation reaction to obtain a compound of general formula I. The method of the present invention has the advantages of simplicity, high efficiency, high yield, reduced cost, and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a trifluoroethyl thioether (sulfoxide) substituted benzene compound and an intermediate used in the method.
Background
The trifluoroethyl thioether (sulfoxide) substituted benzene compound is a novel efficient acaricide. Chinese patent CN110028431A discloses trifluoroethyl thioether (sulfoxide) substituted benzene compounds shown in a general formula I and/or a general formula II, and the compounds show excellent mite killing activity on tetranychus cinnabarinus. The patent publication also discloses a synthetic route and a method of the compound, and a specific reaction formula is shown in a route 1 (G=R 7 =Cl or Br). In the scheme 1, substituted aniline (a compound of a general formula D) is taken as an initial reactant, and is reacted with an o-halogenated methylene acyl halide compound (a compound of a general formula C) to prepare a compound of a general formula B, then the compound of the general formula A is prepared through an oxidation reaction, and finally the compound of the general formula I is prepared through a intramolecular cyclization reaction, or the compound of the general formula B is prepared into a compound of the general formula II through the intramolecular cyclization reaction, and then the compound of the general formula I is prepared through the oxidation reaction.
Route 1
WO2010100189、US2012053052、JP2012519662、EP2403837、CN102341376、WO2013092350、WO2013157229、WO2007131680、WO2015036377、WO2013030319、WO2013030262、WO2013030338、WO2018015852、WO2014202510、WO2014202505 Or WO2015004028 discloses a synthetic route and a method for substituted anilines (compounds of general formula D), the specific reaction formula of which is shown in scheme 2. In the scheme 2, substituted aniline (compound of the general formula VII) is taken as an initial reactant, a compound of the general formula J is prepared through acylation reaction, a compound of the general formula H is prepared through chlorosulfonic acid sulfonation reaction, a compound of the general formula F and/or G is prepared through reduction reaction, a compound of the general formula E is prepared through strong base hydrolysis reaction, and finally a compound of the general formula D is prepared through alkylation reaction.
Route 2
In the method, the steps are complicated, the reaction route is complex, the yield of the final product is low, and the large-scale production is not facilitated. Accordingly, the technical staff is continuously striving to develop new, more advanced, more reasonable and more environment-friendly preparation methods so as to obtain the efficient and safe trifluoroethyl thioether (sulfoxide) substituted benzene acaricide with better quality and lower price.
Disclosure of Invention
Technical problem
The trifluoroethyl thioether (sulfoxide) substituted benzene compound is a high-efficiency and safe novel acaricide, and the inventor explores the traditional preparation process of the trifluoroethyl thioether (sulfoxide) substituted benzene compound in order to find a method suitable for large-scale industrial production of the trifluoroethyl thioether (sulfoxide) substituted benzene compound.
The inventor unexpectedly found that in the process of researching a novel preparation method, substituted aniline (a compound shown in a general formula VII) is adopted as a raw material in the preparation process, and the trifluoroethyl thioether (sulfoxide) substituted benzene compound shown in the general formula I and/or the general formula II can be prepared in high yield through 5 steps of reactions of condensation, sulfonation, reduction, alkylation and oxidation, and the preparation method is suitable for large-scale industrial production.
Thus, the invention provides a novel method for preparing trifluoroethyl thioether (sulfoxide) substituted benzene compounds shown in the general formula I and/or the general formula II on a large scale.
Technical proposal
The invention aims to provide a preparation method of trifluoroethyl thioether (sulfoxide) substituted benzene compounds, which is suitable for large-scale industrial production.
According to a first aspect of the present invention, there is provided a process for preparing a trifluoroethyl sulfide substituted benzene compound represented by the general formula II, which comprises the steps of:
Step 1), condensing the compound of the general formula VII with the compound of the general formula VI to obtain a compound of the general formula V;
Step 2), the compound of the general formula V undergoes sulfonation reaction to obtain a compound of the general formula IV;
step 3) the compound of the general formula IV undergoes a reduction reaction to obtain a compound of the general formula III;
step 4) the compound of the general formula III undergoes alkylation reaction to obtain a compound of the general formula II;
wherein:
R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, C 1-C10 alkyl or C 1-C10 haloalkyl, preferably hydrogen, halogen, cyano, C 1-C6 alkyl or C 1-C6 haloalkyl, more preferably hydrogen, halogen, cyano, C 1-C4 alkyl or C 1-C4 haloalkyl, even more preferably hydrogen, fluorine, chlorine, bromine, cyano or methyl, most preferably R 1 is fluorine, R 2 is selected from methyl or chlorine;
R 3、R4、R5 and R 6 are each independently selected from hydrogen, halogen, cyano, nitro, C 1-C10 alkyl, C 1-C10 haloalkyl, C 1-C10 alkoxy or C 1-C10 haloalkoxy, preferably hydrogen, halogen, cyano, nitro, C 1-C6 alkyl, C 1-C6 haloalkyl, C 1-C6 alkoxy or C 1-C6 haloalkoxy, more preferably hydrogen, halogen, cyano, nitro, C 1-C4 alkyl, C 1-C4 haloalkyl, C 1-C4 alkoxy or C 1-C4 haloalkoxy, even more preferably hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy, most preferably R 3 and R 6 are hydrogen, R 4 and R 5 are each independently selected from hydrogen or fluorine;
R 7 is selected from hydrogen, acetyl or G;
。
According to a second aspect of the present invention, there is provided a process for preparing a trifluoroethyl sulfoxide substituted benzene-like compound represented by the general formula I, which comprises the steps of:
1') preparing a compound of formula II according to the method described in the first aspect above;
2') subjecting a compound of formula II to an oxidation reaction to give a compound of formula I;
wherein R 1 to R 6 are as defined in the first aspect.
For the first and second aspects described above, preferably, the definitions of R 1、R2、R3、R4、R5、R6 and R 7 may be as shown in table 1:
TABLE 1
Preferably, the method comprises the steps of,
In step 1), the compound of formula VII and the compound of formula VI are dissolved in a solvent A and reacted at a temperature of from 0 ℃ to the boiling point of said solvent A to give a compound of formula V, preferably in a molar ratio of the compound of formula VII to the compound of formula VI of from 1:1 to 3, more preferably from 1:1 to 2, even more preferably from 1:1 to 1.5, for example from 1:1 to 1.1;
In step 2), the compound of formula V is reacted with a sulphonating agent at a temperature of-10 ℃ to 200 ℃, preferably-10 ℃ to 160 ℃, to obtain a compound of formula IV, preferably in a molar ratio of the compound of formula V to the sulphonating agent of 1:1 to 100, more preferably 1:1 to 80;
In step 3) the compound of formula IV is reacted with a reducing agent at a temperature of from 0 ℃ to 200 ℃, preferably from 0 ℃ to 150 ℃, more preferably from 0 ℃ to 130 ℃, for example from 0 ℃ to 120 ℃, to produce a compound of formula III, preferably the reducing agent consists of a transition metal and an acid, the acid being selected from organic or inorganic acids, and the molar ratio of the compound of formula IV to the transition metal, the acid being fed in the range of from 1:1 to 50:1 to 100, more preferably from 1:1 to 30:1 to 100, even more preferably from 1:1 to 20:1 to 80, for example from 1:5 to 15:5 to 60;
In step 4) the compound of formula III is reacted with a halogenating agent or sulfonate, base in solvent B at a temperature from 0 ℃ to the boiling temperature of said solvent B to give a compound of formula II, preferably in a molar ratio of the compound of formula III to the addition of said halogenating agent or sulfonate, base of 1:1-5:1-5, more preferably 1:1-4:1-4, even more preferably 1:1-4:1-3, for example 1:1-3:1-2;
Preferably, in step 2'), the compound of formula II is reacted with an oxidizing agent in a solvent C at a temperature of from-10 ℃ to the boiling point of said solvent C to produce a compound of formula I, preferably in a molar ratio of the compound of formula II to the addition of said oxidizing agent of from 1:1 to 10, more preferably from 1:1 to 8, even more preferably from 1:1 to 6, for example from 1:1 to 5.
Preferably, the solvent a is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diglyme, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, acetonitrile, tetrahydrofuran, dioxane, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide.
Preferably, the sulphonating agent is selected from one or more of chlorosulphonic acid, concentrated sulphuric acid, oleum, sulphur trioxide and sulphur monochloride.
Preferably, the transition metal is selected from zinc, iron, copper or nickel or a mixture of zinc, iron, copper and nickel mixed in any proportion, and the acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and nitric acid.
Preferably, the halogenated reagent is selected from trifluoroiodoethane, and the sulfonate is selected from one or more of methanesulfonic acid 2, 2-trifluoroethyl ester, benzenesulfonic acid 2, 2-trifluoroethyl ester or 2, 2-trifluoro-p-toluenesulfonic acid ethyl ester.
Preferably, the base is selected from one or more of trimethylamine, triethylamine, pyridine, DBU, N-diisopropylethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide.
Preferably, the solvent B is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diglyme, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, water, acetonitrile, tetrahydrofuran, dioxane, N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.
Preferably, the oxidizing agent is selected from one or more of m-chloroperoxybenzoic acid, hydrogen peroxide or sodium (meta) periodate.
Preferably, the solvent C is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diglyme, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, water, acetonitrile, tetrahydrofuran, dioxane, N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.
Preferably, in the reaction of step 3), red phosphorus and iodine are further added.
Further preferably, the molar ratio of the compound of formula IV to red phosphorus, iodine is from 1:1 to 10:0.02 to 0.2, more preferably from 1:2 to 8:0.05 to 0.15, even more preferably from 1:2 to 6:0.05 to 0.1.
According to a third aspect of the present invention there is provided a compound having the structure of formula III:
wherein:
R 1 to R 7 are as defined above.
According to a fourth aspect of the present invention there is provided a compound having the structure shown in formula IV:
wherein:
r 1 to R 6 are as defined above.
In the synthetic methods given above and in the definition of groups in the compounds of the general formulae, the terms used in the collection are generally defined as follows:
Halogen means fluorine, chlorine, bromine or iodine;
Alkyl refers to straight or branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl or the different butyl isomers;
haloalkyl refers to straight-chain or branched alkyl groups in which the hydrogen atoms on the alkyl groups may be partially or fully substituted with halogen, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl and the like;
alkoxy refers to a straight or branched chain alkyl group attached to the structure via an oxygen atom linkage, such as methoxy, ethoxy, t-butoxy, and the like;
haloalkoxy means that hydrogen atoms on the alkoxy group may be partially or fully substituted by halogen, such as chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, trifluoroethoxy, and the like.
Advantageous effects
Compared with the prior art, the invention has the following advantages:
1. The synthesis route is short, the prior art takes substituted aniline (compound of the general formula VII) as an initial reactant, the compound of the general formula II can be prepared by 7 steps of reaction, and the compound of the general formula I can be prepared by 8 steps of reaction, and the invention also takes substituted aniline (compound of the general formula VII) as an initial reactant, and the compound of the general formula II can be prepared by 4 steps of reaction, and the compound of the general formula I can be prepared by 5 steps of reaction.
2. The reaction yields in the steps are high, that is, the yield of step 1) (the compound of the general formula V is prepared from the compound of the general formula VII (the maximum of the embodiment of the invention is 96%) in the method of the invention is more than 90%, the yield of step 2) (the compound of the general formula IV is prepared from the compound of the general formula V (the maximum of the embodiment of the invention is 94%), the yield of step 3) (the compound of the general formula III is prepared from the compound of the general formula IV (the maximum of the embodiment of the invention is 96%), the yield of step 4) (the compound of the general formula II is prepared from the compound of the general formula III (the maximum of the embodiment of the invention is 94.6%) in the method of the invention is more than 85%, and the yield of the compound of the general formula I is prepared from the compound of the general formula II (the embodiment of the invention is the maximum of 94.2%).
3. In the reduction reaction of preparing the compound in the general formula III from the compound in the general formula IV, the reduction of the sulfonyl chloride group (Part A) and the reduction of the carbonyl group (Part B) are creatively realized by one-step reduction, and the method has the advantages of simplicity, high efficiency, high yield, cost reduction and the like.
Detailed Description
The following examples are provided to illustrate in detail the preparation of trifluoroethyl sulfide (sulfoxide) -substituted benzene compounds of the general formula I and/or the general formula II of the present invention, but are not meant to limit the present invention. Various changes and modifications may be made within the scope of the present invention as defined in the appended claims.
EXAMPLE 1 preparation of 2- (2-fluoro-4-methylphenyl) isoindole-1, 3-dione
2-Fluoro-4-methylaniline (10 g, 0.08 mol), 250 mL toluene and phthalic anhydride (12.4 g, 0.084 mol) were added to a 500 mL reaction flask and water was refluxed with stirring. After 8 hours of reaction, the reaction mixture was cooled to room temperature. The reaction solution was concentrated to dryness, and 200 mL ethyl acetate and 200 mL water were added for extraction, and washed with a saturated sodium bicarbonate solution and a saturated saline solution in this order, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to give 20 g of 2- (2-fluoro-4-methylphenyl) isoindole-1, 3-dione as a white solid, the quantitative content of which by HPLC was 98.2%, corresponding to a yield of 96%.
EXAMPLE 2 preparation of 5- (1, 3-Dioxiisoindol-2-yl) -4-fluoro-2-toluenesulfonyl chloride
Chlorosulfonic acid (411 g, 3.55 mol) is added into a 500 mL three-mouth bottle, cooled to 0-5 ℃, and 2- (2-fluoro-4-methylphenyl) isoindole-1, 3-dione (15 g, 0.059 mol) is added in batches, and the reaction temperature is controlled to be not more than 5 ℃. After 30 minutes of reaction, the reaction solution is slowly dripped into ice water to separate out white solid, and suction filtration is carried out, a filter cake is taken and dried to obtain 20g of white solid 5- (1, 3-dioxoisoindol-2-yl) -4-fluoro-2-toluenesulfonyl chloride, the quantitative content of HPLC is 98.5%, and the corresponding yield is 94%.
EXAMPLE 3 preparation of 5- (1, 3-Dioxiisoindol-2-yl) -4-fluoro-2-toluenesulfonyl chloride
Chlorosulfonic acid (35.4 g, 303.8 mmol) was added to a100 mL three-port flask, 2- (2-fluoro-4-methylphenyl) isoindole-1, 3-dione (1 g, 3.9 mmol) was added in portions, followed by warming to 150 ℃. After 10 minutes of reaction, the reaction solution was cooled to room temperature. And slowly dripping the reaction solution into ice water to precipitate a white solid, carrying out suction filtration, taking and drying a filter cake to obtain 1.24 g of white solid 5- (1, 3-dioxoisoindol-2-yl) -4-fluoro-2-toluenesulfonyl chloride, wherein the quantitative content of HPLC is 98.6%, and the corresponding yield is 88%.
EXAMPLE 4 preparation of 5- (1, 3-Dioxiisoindol-2-yl) -4-fluoro-2-toluenesulfonyl chloride
Chlorosulfonic acid (45.6 g, 0.39 mol) is added into a 500 mL three-mouth bottle, cooled to 0-5 ℃, and 2- (2-fluoro-4-methylphenyl) isoindole-1, 3-dione (10 g, 39 mmol) is added in batches, and the reaction temperature is controlled to be not more than 10 ℃. Then the reaction temperature is raised to 30 ℃, after the reaction is carried out for 1 hour, the reaction solution is slowly dripped into ice water, white solid is separated out, suction filtration is carried out, filter cakes are taken and dried to obtain 12.6 g of white solid 5- (1, 3-dioxoisoindol-2-yl) -4-fluoro-2-toluenesulfonyl chloride, the quantitative content of HPLC is 98.3%, and the corresponding yield is 89%.
EXAMPLE 5 preparation of 5- (1, 3-Dioxiisoindol-2-yl) -4-fluoro-2-toluenesulfonyl chloride
Chlorosulfonic acid (22.8 g, 195 mmol) is added into a 500mL three-mouth bottle, the temperature is reduced to 0-5 ℃,2- (2-fluoro-4-methylphenyl) isoindole-1, 3-dione (10 g, 39 mmol) is added in batches, and the reaction temperature is controlled to be not more than 10 ℃. Then the reaction temperature is raised to 40 ℃ for 2 hours, the reaction solution is slowly dripped into ice water to precipitate white solid, and suction filtration is carried out, filter cakes are taken and dried to obtain 12.3 g of white solid 5- (1, 3-dioxoisoindol-2-yl) -4-fluoro-2-toluenesulfonyl chloride, the quantitative content of HPLC is 98.1%, and the corresponding yield is 87%.
EXAMPLE 6 preparation of 5- (1, 3-Dioxyisoindol-2-yl) -4-fluoro-2-toluenesulfonyl chloride
Chlorosulfonic acid (13.7 g, 117 mmol) is added into a 500 mL three-mouth bottle, the temperature is reduced to 0-5 ℃,2- (2-fluoro-4-methylphenyl) isoindole-1, 3-dione (10 g, 39 mmol) is added in batches, and the reaction temperature is controlled to be not more than 10 ℃. Then the reaction temperature is raised to 50 ℃, after the reaction is carried out for 3 hours, the reaction solution is slowly dripped into ice water, white solid is separated out and filtered by suction, and the filter cake is taken and dried to obtain 12 g of white solid 5- (1, 3-dioxoisoindol-2-yl) -4-fluoro-2-toluenesulfonyl chloride, the quantitative content of HPLC is 98 percent, and the corresponding yield is 85 percent.
EXAMPLE 7 preparation of 2- (2-fluoro-5-mercapto-4-methylphenyl) isoindol-1-one
To a 100 mL reaction flask was added 5- (1, 3-dioxoisoindol-2-yl) -4-fluoro-2-tosyl chloride (1 g, 2.8 mmol), acetic acid (10.2 g, 170 mmol), zinc powder (1.85 g, 28 mmol) was added with stirring, and after reaction at 120℃for 30 minutes, the reaction solution was filtered while it was hot. Ethyl acetate 10 mL was rinsed, the reaction was concentrated to dryness, 100 mL ethyl acetate and 100 mL water were added to extract, the mixture was washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to give 0.73 g of 2- (2-fluoro-5-mercapto-4-methylphenyl) isoindol-1-one as a white solid, with a quantitative content of 98.7% by hplc, corresponding to a yield of 95%.
EXAMPLE 8 preparation of 2- (2-fluoro-5-mercapto-4-methylphenyl) isoindol-1-one and S- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethanesulfate
To a 100 mL reaction flask was added 5- (1, 3-dioxoisoindol-2-yl) -4-fluoro-2-tosyl chloride (1 g, 2.8 mmol), acetic acid (10.2 g, 170 mmol), zinc powder (1.85 g, 28 mmol) was added with stirring, and after reacting at 120℃for 5 hours, the reaction solution was filtered while it was hot. Ethyl acetate 10 mL was rinsed, the reaction solution was concentrated to dryness, 100 mL ethyl acetate and 100 mL water were added, the mixture was washed with saturated brine, the organic phase was dried over anhydrous magnesium sulfate and concentrated, and the white solid, 0.21 g of 2- (2-fluoro-5-mercapto-4-methylphenyl) isoindol-1-one, was separated by column chromatography, and the quantitative content of HPLC was 98.4%, corresponding to 27% yield, white solid, 0.52 g% of S- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethyl sulfate, corresponding to 58% of HPLC, and total yield of 2- (2-fluoro-5-mercapto-4-methylphenyl) isoindol-1-one and S- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethyl sulfate was 85%.
Example 9:S preparation of- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethanesulfate
To a 100mL reaction flask was added 5- (1, 3-dioxoisoindol-2-yl) -4-fluoro-2-tosyl chloride (1 g,2.8 mmol), acetic acid (10.2 g, 170 mmol), zinc powder (1.85 g, 28 mmol) was added with stirring, and after a reaction time of 36 hours at 120 ℃, the reaction solution was filtered while it was hot. Ethyl acetate 10mL was rinsed, the reaction solution was concentrated to dryness, 100mL ethyl acetate and 100mL water were added to extract, the mixture was washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to give 0.75 g of S- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethyl sulfate as a white solid, the quantitative content of hplc was 98.7%, corresponding to a yield of 84%.
EXAMPLE 10 preparation of 2- (2-fluoro-5-mercapto-4-methylphenyl) isoindol-1-one and S- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethanesulfate
To a 100 mL reaction flask was added 5- (1, 3-dioxoisoindol-2-yl) -4-fluoro-2-tosyl chloride (1 g, 2.8 mmol), acetic acid (10.2 g, 170 mmol) and acetic anhydride (1.1 g, 11.2 mmol), zinc powder (1.85 g, 28 mmol) was added with stirring, and after reacting at 120℃for 5 hours, the reaction solution was filtered while it was hot. Ethyl acetate 10 mL was rinsed, the reaction solution was concentrated to dryness, 100 mL ethyl acetate and 100 mL water were added to extract, the mixture was washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate and concentrated, and the white solid, 0.15 g of 2- (2-fluoro-5-mercapto-4-methylphenyl) isoindol-1-one, was separated by column chromatography, and its quantitative content by hplc was 98.1%, corresponding to 19%, 0.60 g of white solid, S- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethylsulfate, its quantitative content by hplc was 98.2%, corresponding to 67%. The total yield of 2- (2-fluoro-5-mercapto-4-methylphenyl) isoindol-1-one and S- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethanesulfate was 86%.
EXAMPLE 11 preparation of S- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethanesulfate
To a 100mL reaction flask was added 5- (1, 3-dioxoisoindol-2-yl) -4-fluoro-2-tosyl chloride (1 g, 2.8 mmol), acetic acid (10.2 g, 170 mmol) and acetic anhydride (1.1 g, 11.2 mmol), zinc powder (1.85 g, 28 mmol) was added with stirring, and after a reaction time of 36 hours at 120 ℃, the reaction solution was filtered while it was hot. Ethyl acetate 10 mL was rinsed, the reaction solution was concentrated to dryness, 100mL ethyl acetate and 100mL water were added to extract, the mixture was washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to give 0.75 g of S- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethyl sulfate as a white solid, which was 98.7% quantitatively by hplc, corresponding to a yield of 88%.
EXAMPLE 12 preparation of S- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethanesulfate
5- (1, 3-Dioxisoindol-2-yl) -4-fluoro-2-tosyl chloride (3 g, 8.5 mmol), acetic acid (6.9 g, 115.6 mmol), acetic anhydride (3.45 g, 33.8 mmol), red phosphorus (1.59 g, 51.3 mmol), iodine (0.21 g, 0.8 mmol) were weighed into a 250 mL reaction flask and warmed to reflux. After 10 minutes of reaction, zinc powder (5.55 g, 85 mmol) and acetic acid (27 g, 449.6 mmol) were added and the reflux reaction was continued for 2 hours. The reaction solution was filtered under heat, the residue was washed with ethyl acetate, the filtrate and the washings were combined, concentrated under reduced pressure, the residue was extracted with 200 mL ethyl acetate and 200 mL water, the organic phase was washed with saturated sodium bicarbonate solution and saturated brine in this order, the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 2.6 g of S- (4-fluoro-2-methyl-5- (1-oxoisoindol-2-yl) phenyl) ethyl sulfate as a white solid, the quantitative content of HPLC was 98.9%, corresponding to a yield of 95%.
EXAMPLE 13 preparation of 2- (2-fluoro-5-mercapto-4-methylphenyl) isoindol-1-one
S- (4-fluoro-2-methyl-5- (1-oxyisoindol-2-yl) phenyl) ethyl sulfate (1 g, 3.17 and mmol), 10 mL tetrahydrofuran and formaldehyde sodium sulfoxylate (0.41 and g and 3.49 and mmol) are weighed and added into a 50 mL reaction bottle, the temperature is reduced to 0-5 ℃, dropwise adding of sodium hydroxide aqueous solution (0.25 and g are dissolved in 5 and mL water) is started, the temperature-controlled reaction is not more than 10 ℃, and after the dropwise adding is finished, the heat-preserving reaction is continued for 30 minutes. 50 mL water and 50 mL methylene chloride were added to the reaction mixture to extract the mixture. Concentrated hydrochloric acid (0.65 g,6.6 mmol) is added into the water phase, stirring is continued after the dripping is finished, white solid is continuously separated out, 50 mL methylene dichloride is added for extraction, organic phase is dried and concentrated, and 0.76 g white solid 2- (2-fluoro-5-mercapto-4-methylphenyl) isoindol-1-one is obtained, the quantitative content of HPLC is 98%, and the corresponding yield is 86%.
EXAMPLE 14 preparation of 2' - (dithiobis (6-fluoro-4-methyl-3, 1-phenylene)) bis (isoindol-1-one)
Weighing 2- (2-fluoro-5-mercapto-4-methylphenyl) isoindol-1-one (1 g, 3.66 mmol), adding 10 mL tetrahydrofuran into a 50mL reaction bottle, cooling to 0-5 ℃, beginning to dropwise add sodium hydroxide aqueous solution (0.29 g is dissolved in 5mL water), controlling the temperature to react at not more than 10 ℃, and continuing to perform heat preservation reaction for 30 minutes after the dropwise addition is finished. 50mL water and 50mL methylene chloride are added into the reaction solution for extraction, and organic phase is dried and concentrated to obtain 0.87g white solid 2,2' - (dithiodiacylbis (6-fluoro-4-methyl-3, 1-phenylene)) bis (isoindol-1-one), the quantitative content of HPLC is 98.2 percent, and the corresponding yield is 85.7 percent.
EXAMPLE 15 preparation of 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
2- (2-Fluoro-5-mercapto-4-methylphenyl) isoindol-1-one (1 g, 3.7 mmol), potassium carbonate (1.02 g, 7.4 mmol), 10 mL of N, N-dimethylformamide, sodium formaldehyde sulfoxylate (0.48 g, 4.1 mmol), 2-iodo-1, 1-trifluoroethane (0.85 g, 4.0 mol) were weighed into a 100 mL three-necked flask, reacted at room temperature for 2 hours, 50 mL ethyl acetate and 50 mL water were added for extraction, after organic phase drying and concentration, a small amount of petroleum ether was added for stirring and suction filtration, and the filter cake was collected and dried to obtain 1.18 g of white solid 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) phenyl) isoindol-1-one with a quantitative content of 98.7% by HPLC, corresponding yield of 91%.
EXAMPLE 16 preparation of 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
2- (2-Fluoro-5-mercapto-4-methylphenyl) isoindol-1-one (1.0 g, 3.7 mmol), potassium hydroxide (0.42 g, 7.4 mmol), 10 mL N, N-dimethylformamide, sodium formaldehyde sulfoxylate (0.48 g, 4.1 mmol), 2-iodo-1, 1-trifluoroethane (0.85 g, 4.1 mmol) were weighed into a 100 mL three-necked flask, reacted at room temperature for 2 hours, then 50 mL ethyl acetate and 50 mL water were added for extraction, after organic phase drying and concentration, a small amount of petroleum ether was added for stirring and suction filtration, and the filter cake was collected and dried to obtain 1.21 g of white solid 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) phenyl) isoindol-1-one with a quantitative content of 98.7% by HPLC, corresponding yield of 93%.
EXAMPLE 17 preparation of 2- (2-fluoro-4-methyl-5- ((2, 2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
2- (2-Fluoro-5-mercapto-4-methylphenyl) isoindol-1-one (1 g, 3.7 mmol), potassium hydroxide (0.42 g, 7.4 mmol), sodium formaldehyde sulfoxylate (0.48 g, 4.1 mmol), 10 mL acetone, 2-iodo-1, 1-trifluoroethane (0.85 g, 4.0 mmol) were weighed into a 100 mL three-necked flask, reacted at room temperature for 2 hours, concentrated under reduced pressure, the residue was extracted with 50 mL ethyl acetate, 50 mL water, and after organic phase drying and concentration, a small amount of petroleum ether was added, stirred and suction filtered, and the filter cake was collected and dried to obtain white solid 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) thio) isoindol-1-one (1.16 g, hplc quantitative content 98.7% corresponding to 89% yield.
EXAMPLE 18 preparation of 2- (2-fluoro-4-methyl-5- ((2, 2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
S- (4-fluoro-2-methyl-5- (1-oxyisoindol-2-yl) phenyl) ethyl sulfate (0.74 g, 2.3 mmol), 20 mL N, N-dimethylformamide, sodium formaldehyde sulfoxylate (0.31 g, 2.6 mmol), anhydrous potassium carbonate (0.72 g, 5.2 mmol) and trifluoroiodoethane (0.54 g, 2.6 mmol) were weighed into a 100 mL three-necked flask, and the reaction system was warmed to 50 ℃. After 2 hours of reaction, the reaction mixture was cooled to room temperature. Adding 50 mL ethyl acetate and 50 mL water for extraction, adding a small amount of petroleum ether for stirring and suction filtration after organic phase drying and concentration, collecting a filter cake and drying to obtain 0.72. 0.72 g white solid 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one, wherein the quantitative content of HPLC is 98.5 percent and the corresponding yield is 84 percent.
EXAMPLE 19 preparation of 2- (2-fluoro-4-methyl-5- ((2, 2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
2, 2' - (Dithiobis (6-fluoro-4-methyl-3, 1-phenylene)) bis (isoindol-1-one) (1 g, 1.8 mmol), 20. 20 mL N, N-dimethylformamide, sodium formaldehyde sulfoxylate (0.18 g, 1.5 mmol), anhydrous potassium carbonate (0.50 g, 3.6 mmol), and trifluoroiodoethane (0.84 g, 4.0 mmol) were weighed into a 100mL three-necked flask, and the reaction system was warmed to 50 ℃. After 2 hours of reaction, the reaction mixture was cooled to room temperature. Adding 50mL ethyl acetate and 50mL water for extraction, adding a small amount of petroleum ether for stirring and suction filtration after organic phase drying and concentration, collecting a filter cake and drying to obtain 1.12 g white solid 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one, wherein the quantitative content of HPLC is 98.9 percent, and the corresponding yield is 86 percent.
EXAMPLE 20 preparation of 2- (2-fluoro-4-methyl-5- ((2, 2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
2- (2-Fluoro-4-methyl-5- ((2, 2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one (2.6 g, 8.3 mmol), N-dimethylformamide 50 mL, sodium formaldehyde sulfoxylate (1.1 g, 9.3 mol), anhydrous potassium carbonate (3.4 g, 24.6 mmol), ethyl 2,2, 2-trifluoro-p-toluenesulfonate (2.3 g, 9.1 mmol) were weighed into a 100 mL three-necked flask and the reaction system was warmed to 50 ℃. After 16 hours of reaction, the reaction mixture was cooled to room temperature. The reaction solution is added with 50 mL ethyl acetate and 50 mL water for extraction, the organic phase is washed by saturated sodium bicarbonate, the organic phase is concentrated by drying, a small amount of petroleum ether is added, the mixture is stirred and filtered by suction, a filter cake is collected and dried, and 2.76 g white solid 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one is obtained, the quantitative content of HPLC is 98.5 percent, and the corresponding yield is 94 percent.
EXAMPLE 21 preparation of 2- (2-fluoro-4-methyl-5- ((2, 2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
2- (2-Fluoro-5-mercapto-4-methylphenyl) isoindol-1-one (3 g, 11 mmol), N-dimethylformamide 50mL, sodium formaldehyde sulfoxylate (1.4 g, 12.1 mol), anhydrous potassium carbonate (3 g, 22 mmol), benzenesulfonic acid 2,2, 2-trifluoroethyl ester (2.6 g, 12.1 mmol) were weighed into a 100 mL three-necked flask, and the reaction system was warmed to 50 ℃. After 12 hours of reaction, the reaction mixture was cooled to room temperature. The reaction solution is added with 50mL ethyl acetate and 50mL water for extraction, the organic phase is washed by saturated sodium bicarbonate, the organic phase is concentrated by dryness, a small amount of petroleum ether is added, the mixture is stirred and filtered by suction, a filter cake is collected and dried, and 3.74 g white solid 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one is obtained, the quantitative content of HPLC is 98.6 percent, and the corresponding yield is 94.6 percent.
EXAMPLE 22 preparation of 2- (2-fluoro-4-methyl-5- ((2, 2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
2- (2-Fluoro-5-mercapto-4-methylphenyl) isoindol-1-one (3 g,11 mmol), N-dimethylformamide 50 mL, sodium formaldehyde sulfoxylate (1.4 g, 12.1 mol), anhydrous potassium carbonate (3 g, 22 mmol), methanesulfonic acid 2,2, 2-trifluoroethyl ester (2.15 g, 12.1 mmol) were weighed into a 100mL three-necked flask, and the reaction system was warmed to 50 ℃. After 20 hours of reaction, the reaction mixture was cooled to room temperature. The reaction solution is added with 50 mL ethyl acetate and 50 mL water for extraction, the organic phase is washed by saturated sodium bicarbonate, the organic phase is concentrated by drying, a small amount of petroleum ether is added, the mixture is stirred and filtered by suction, a filter cake is collected and dried, and 3.66 g white solid 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one is obtained, the quantitative content of HPLC is 98.3 percent, and the corresponding yield is 92.3 percent.
EXAMPLE 23 preparation of 2- (2-fluoro-4-methyl-5- ((2, 2, 2-trifluoroethyl) sulfoxide) phenyl) isoindol-1-one
2- (2-Fluoro-4-methyl-5- ((2, 2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one (1 g, 2.8 mmol) is weighed into a 100mL three-necked flask, 30mL methylene chloride is added, the system is placed in an ice-water bath, and m-chloroperoxybenzoic acid (0.57 g, 2.8 mmol, 85% purity) is added in batches at a temperature of 0-5 ℃. After 3 hours of reaction, 50 mL dichloromethane was added for dilution, washed sequentially with aqueous sodium thiosulfate and saturated sodium bicarbonate solution, the organic phase was dried over anhydrous magnesium sulfate for filtration and concentrated to give 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) sulfoxide) phenyl) isoindol-1-one as a white solid 0.9g, with a quantitative content of 98.6% by HPLC, corresponding to a yield of 88%.
EXAMPLE 24 preparation of 2- (2-fluoro-4-methyl-5- ((2, 2, 2-trifluoroethyl) sulfoxide) phenyl) isoindol-1-one
2- (2-Fluoro-4-methyl-5- ((2, 2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one (1 g, 2.8 mmol), 50mL dichloromethane, H 2O2 (1.59 g, 30% by mass concentration, 14 mmol), acetylacetone (0.28 g, 2.8 mmol), stannous chloride dihydrate (0.13 g, 0.56 mmol) were weighed into a 100mL reaction flask and reacted at 25 ℃ for 24 hours. 50mL methylene chloride is added for dilution, the mixture is washed by a sodium thiosulfate aqueous solution and a saturated sodium bicarbonate solution in sequence, and an organic phase is dried by anhydrous magnesium sulfate, filtered and concentrated to obtain white solid 2- (2-fluoro-4-methyl-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one 1g, wherein the quantitative content of the HPLC is 98.5 percent, and the corresponding yield is 94.2 percent.
EXAMPLE 25 preparation of 2- (4-chloro-2-fluorophenyl) isoindole-1, 3-dione
2-Fluoro-4-chloroaniline (10 g, 68.9 mmol), 250 mL toluene and phthalic anhydride (10.6 g, 71.6 mmol) were added to a 500 mL reaction flask and water was refluxed with stirring. After 12 hours of reaction, the reaction mixture was cooled to room temperature. The reaction system was concentrated to dryness, 200 mL ethyl acetate and 200 mL water were added for extraction, and the mixture was washed with saturated sodium bicarbonate solution and saturated brine in this order, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to give 2- (4-chloro-2-fluorophenyl) isoindole-1, 3-dione as a white solid 18 g, an HPLC quantitative content of 98.2% and a corresponding yield of 93%.
EXAMPLE 26 preparation of 2-chloro-5- (1, 3-dioxoisoindol-2-yl) -4-fluorobenzenesulfonyl chloride
Chlorosulfonic acid (457.6 g, 3.92 mol) is added into a 1000 mL three-mouth bottle, 2- (4-chloro-2-fluorophenyl) isoindole-1, 3-dione (18 g, 65.4 mmol) is added in batches, the system is heated to 70 ℃, after 3 hours of reaction, the reaction liquid is slowly dripped into ice water, white solid is separated out, suction filtration is carried out, a filter cake is taken and dried to obtain 21 g of white solid 2-chloro-5- (1, 3-dioxoisoindol-2-yl) -4-fluorobenzenesulfonyl chloride, the quantitative content of HPLC is 98.2%, and the corresponding yield is 89%.
EXAMPLE 27 preparation of 2-chloro-5- (1, 3-dioxoisoindol-2-yl) -4-fluorobenzenesulfonyl chloride
Chlorosulfonic acid (4.2 g, 36, mmol) was added to a 50mL three-necked flask, 2- (4-chloro-2-fluorophenyl) isoindole-1, 3-dione (1 g, 3.6 mmol) was added in portions, followed by warming to 120 ℃. After 10 minutes of reaction, the reaction solution was cooled to room temperature. The reaction solution is slowly dripped into ice water to separate out white solid, and suction filtration is carried out, a filter cake is taken and dried to obtain 1.26 g of white solid 2-chloro-5- (1, 3-dioxoisoindol-2-yl) -4-fluorobenzenesulfonyl chloride, the quantitative content of HPLC is 98.2%, and the corresponding yield is 91.2%.
EXAMPLE 28 preparation of 2- (4-chloro-2-fluoro-5-mercaptophenyl) isoindol-1-one
2-Chloro-5- (1, 3-dioxoisoindol-2-yl) -4-fluorobenzenesulfonyl chloride (1 g, 2.7 mmol) and acetic acid (9.6 g, 160.8 mmol) were added to a 100 mL reaction flask, zinc powder (1.76 g, 27 mmol) was added with stirring, and after reaction at 120℃for 30 minutes, the reaction solution was filtered while it was hot. Ethyl acetate 10 mL was rinsed, the reaction was concentrated to dryness, 100 mL ethyl acetate and 100 mL water were added to extract, the mixture was washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to give 0.75 g of 2- (4-chloro-2-fluoro-5-mercaptophenyl) isoindol-1-one as a white solid, with a quantitative content of 98.7% by hplc, corresponding to a yield of 96%.
EXAMPLE 29 preparation of 2- (4-chloro-2-fluoro-5-mercaptophenyl) isoindol-1-one and S- (2-chloro-4-fluoro-5- (1-oxoisoindol-2-yl) phenyl) ethanesulfate
2-Chloro-5- (1, 3-dioxoisoindol-2-yl) -4-fluorobenzenesulfonyl chloride (1 g, 2.7 mmol) and acetic acid (9.6 g, 160.8 mmol) were added to a 100mL reaction flask, zinc powder (1.76 g, 27 mmol) was added with stirring, and after reacting at 120℃for 5 hours, the reaction solution was filtered while it was hot. Ethyl acetate 10 mL was rinsed, the reaction solution was concentrated to dryness, 100mL ethyl acetate and 100mL water were added to extract, the mixture was washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate and concentrated, and the white solid, 0.2 g of 2- (4-chloro-2-fluoro-5-mercaptophenyl) isoindol-1-one, was separated by column chromatography, and its quantitative content by hplc was 98.3%, corresponding to 25%, white solid, 0.58 g of S- (2-chloro-4-fluoro-5- (1-oxoisoindol-2-yl) phenyl) ethylsulfate, its quantitative content by hplc was 98.5%, corresponding to 65%. The total yield of 2- (4-chloro-2-fluoro-5-mercaptophenyl) isoindol-1-one and S- (2-chloro-4-fluoro-5- (1-oxoisoindol-2-yl) phenyl) ethanesulfate was 90%.
EXAMPLE 30 preparation of S- (2-chloro-4-fluoro-5- (1-oxoisoindol-2-yl) phenyl) ethanesulfate
2-Chloro-5- (1, 3-dioxoisoindol-2-yl) -4-fluorobenzenesulfonyl chloride (1 g, 2.7 mmol) and acetic acid (9.6 g, 160.8 mmol) were added to a 100mL reaction flask, zinc powder (1.76 g, 27 mmol) was added with stirring, and after reaction at 120℃for 36 hours, the reaction solution was filtered while it was hot. Ethyl acetate 10mL was rinsed, the reaction solution was concentrated to dryness, 100mL ethyl acetate and 100mL water were added to extract, the mixture was washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to give 0.81 g of S- (2-chloro-4-fluoro-5- (1-oxoisoindol-2-yl) phenyl) ethyl sulfate as a white solid, the quantitative content of hplc was 98.2%, corresponding to a yield of 90%.
EXAMPLE 31 preparation of S- (2-chloro-4-fluoro-5- (1-oxoisoindol-2-yl) phenyl) ethanesulfate
2-Chloro-5- (1, 3-dioxoisoindol-2-yl) -4-fluorobenzenesulfonyl chloride (10 g, 26.8 mmol), acetic acid (21.9 g, 364.6 mmol), acetic anhydride (10.94 g, 107.2 mmol), red phosphorus (4.98 g, 160.8 mmol) and iodine (0.68 g, 2.6 mmol) were weighed into a 250 mL reaction flask, and the reaction system was warmed up to reflux. After 1 hour of reaction, zinc powder (17.5 g, 267.6 mmol) and acetic acid (96.6 g, 1.6 mol) were added and the reflux reaction was continued for 12 hours. The reaction solution was filtered by heating, the residue was washed with ethyl acetate, the filtrate and the washings were combined, concentrated under reduced pressure, the residue was extracted with ethyl acetate and water, the organic phase was washed with a saturated sodium hydrogencarbonate solution and a saturated brine in this order, the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give 8.2g of S- (2-chloro-4-fluoro-5- (1-oxyisoindol-2-yl) phenyl) ethyl sulfate as a white solid, the quantitative content of HPLC was 99.1%, corresponding to a yield of 90%.
EXAMPLE 32 preparation of 2- (4-chloro-2-fluoro-5-mercaptophenyl) isoindol-1-one
S- (2-chloro-4-fluoro-5- (1-oxyisoindol-2-yl) phenyl) ethyl sulfate (1 g, 2.98 mmol), 10mL tetrahydrofuran and formaldehyde sodium sulfoxylate (0.39 g, 3.28 mmol) are weighed and added into a 50 mL reaction bottle, the temperature is reduced to 0-5 ℃, dropwise adding of sodium hydroxide aqueous solution (0.25 g is dissolved in 5mL of water) is started, the temperature control reaction is not more than 10 ℃, and after the dropwise adding, the heat preservation reaction is continued for 30 minutes. 50 mL water and 50 mL methylene chloride were added to the reaction mixture to extract the mixture. Concentrated hydrochloric acid (0.65 g,6.6 mmol) is added into the water phase, stirring is continued after the dripping is finished, white solid is continuously separated out, 50 mL methylene dichloride is added for extraction, organic phase is dried and concentrated, and 0.73 g white solid 2- (4-chloro-2-fluoro-5-mercaptophenyl) isoindol-1-one is obtained, the quantitative content of HPLC is 98%, and the corresponding yield is 84%.
EXAMPLE 33 preparation of 2,2' - (dithiodiacylbis (4-chloro-6-fluoro-3, 1-phenylene)) bis (isoindol-1-one)
Weighing 2- (4-chloro-2-fluoro-5-mercaptophenyl) isoindol-1-one (1 g, 3.41 mmol), adding 10 mL tetrahydrofuran into a 50 mL reaction bottle, cooling to 0-5 ℃, beginning to dropwise add sodium hydroxide aqueous solution (0.29 g is dissolved in 5mL of water), controlling the temperature to react at not more than 10 ℃, and continuing to perform heat preservation reaction for 30 minutes after the dropwise addition is finished. 50 mL water and 50 mL methylene chloride are added into the reaction solution for extraction, and organic phase is dried and concentrated to obtain 0.87. 0.87 g white solid 2,2' - (dithiodiacylbis (4-chloro-6-fluoro-3, 1-phenylene)) bis (isoindol-1-one), wherein the quantitative content of HPLC is 98.2 percent, and the corresponding yield is 87 percent.
EXAMPLE 34 preparation of 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
2- (4-Chloro-2-fluoro-5-mercaptophenyl) isoindol-1-one (1 g, 3.4 mmol), potassium carbonate (0.94 g, 6.8 mmol), 10mL of N, N-dimethylformamide, sodium formaldehyde sulfoxylate (0.44 g, 3.7 mmol), 2-iodo-1, 1-trifluoroethane (0.78 g, 3.7 mol) were weighed into a 100 mL three-necked flask, reacted at room temperature for 2 hours, 50 mL ethyl acetate and 50 mL water were added for extraction, after organic phase drying and concentration, a small amount of petroleum ether was added for stirring and suction filtration, and the filter cake was collected and dried to obtain 1.23g of white solid 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) phenyl) isoindol-1-one with a quantitative content of 98.7% by HPLC and a corresponding yield of 93%.
EXAMPLE 35 preparation of 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
S- (2-chloro-4-fluoro-5- (1-oxyisoindol-2-yl) phenyl) ethyl sulfate (1 g, 3.0 mmol), N-dimethylformamide 20 mL, sodium formaldehyde sulfoxylate (0.39 g, 3.3 mmol), trifluoroiodoethane (0.69 g, 3.3 mmol) and anhydrous potassium carbonate (0.86 g, 6.2 mmol) were weighed into a 100 mL three-necked flask, and the reaction system was warmed to 50 ℃. After 2 hours of reaction, the reaction mixture was cooled to room temperature. Adding 50mL ethyl acetate and 50mL water for extraction, adding a small amount of petroleum ether for stirring after organic phase drying and concentrating, collecting a filter cake for drying, and obtaining 1.0 g white solid 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one, wherein the quantitative content of HPLC is 98.6 percent and the corresponding yield is 87 percent.
EXAMPLE 36 preparation of 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
2, 2' - (Dithiobis (4-chloro-6-fluoro-3, 1-phenylene)) bis (isoindol-1-one) (1 g, 1.7 mmol), 20. 20 mL N, N-dimethylformamide, sodium formaldehyde sulfoxylate (0.16 g, 1.3 mmol), anhydrous potassium carbonate (0.47 g, 3.4 mmol), and trifluoroiodoethane (0.79 g, 3.76 mmol) were weighed into a 100mL three-necked flask, and the reaction system was warmed to 50 ℃. After 2 hours of reaction, the reaction mixture was cooled to room temperature. Adding 50mL ethyl acetate and 50mL water for extraction, adding a small amount of petroleum ether for stirring and suction filtration after organic phase drying and concentration, collecting a filter cake and drying to obtain 1.1. 1.1 g white solid 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one, wherein the quantitative content of HPLC is 98.5 percent, and the corresponding yield is 84.6 percent.
EXAMPLE 37 preparation of 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
2- (4-Chloro-2-fluoro-5-mercaptophenyl) isoindol-1-one (3 g, 10.2 mmol), N-dimethylformamide 50 mL, sodium formaldehyde sulfoxylate (1.3 g, 11.5 mol), anhydrous potassium carbonate (3.1 g, 22.5 mmol), methanesulfonic acid 2,2, 2-trifluoroethyl ester (2 g, 11.2 mmol) were weighed into a 100 mL three-necked flask, and the reaction system was warmed to 50 ℃. After 22 hours of reaction, the reaction mixture was cooled to room temperature. The reaction solution is added with 50 mL ethyl acetate and 50 mL water for extraction, the organic phase is washed by saturated sodium bicarbonate, the organic phase is concentrated by drying, a small amount of petroleum ether is added, the mixture is stirred and filtered by suction, a filter cake is collected and dried, and 3.45 g white solid 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one is obtained, the quantitative content of HPLC is 98.5 percent, and the corresponding yield is 88.6 percent.
EXAMPLE 38 preparation of 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one
S- (2-chloro-4-fluoro-5- (1-oxyisoindol-2-yl) phenyl) ethyl sulfate (3 g, 8.9 mmol), N-dimethylformamide 50 mL, sodium formaldehyde sulfoxylate (1.16 g, 9.8 mol), anhydrous potassium carbonate (3.7 g, 26.8 mmol), 2,2, 2-trifluoro-p-toluenesulfonic acid ethyl ester (2.5 g, 9.8 mmol) were weighed into a 100 mL three-necked flask, and the reaction system was warmed to 50 ℃. After 16 hours of reaction, the reaction mixture was cooled to room temperature. The reaction solution is added with 50 mL ethyl acetate and 50 mL water for extraction, the organic phase is washed by saturated sodium bicarbonate, the organic phase is concentrated by drying, a small amount of petroleum ether is added, the mixture is stirred and filtered by suction, a filter cake is collected and dried, and 3.19 g white solid 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one is obtained, the quantitative content of HPLC is 98.6 percent, and the corresponding yield is 93.6 percent.
EXAMPLE 39 preparation of 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) sulfinyl) phenyl) isoindol-1-one
2- (4-Chloro-2-fluoro-5- ((2, 2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one (0.5 g, 1.3 mmol) is weighed into a 100 mL three-necked flask, 20 mL dichloromethane is added, the system is placed in an ice-water bath, m-chloroperoxybenzoic acid (0.23 g, 1.3 mmol, 85% purity) is added in batches at a temperature of 0-5 ℃ for 2 hours, 20 mL dichloromethane is added for dilution after reaction, the aqueous solution of sodium thiosulfate and saturated sodium bicarbonate solution are sequentially used for washing, the organic phase is dried and filtered with anhydrous magnesium sulfate, and concentrated to obtain white solid 2- (4-chloro-2-fluoro-5- ((2, 2, 2-trifluoroethyl) sulfinyl) phenyl) isoindol-1-one with a quantitative content of 0.46 g and a corresponding yield of 88% by HPLC.
EXAMPLE 40 preparation of 2- (4-chloro-2-fluoro-5- ((2, 2-trifluoroethyl) sulfinyl) phenyl) isoindol-1-one
2- (4-Chloro-2-fluoro-5- ((2, 2-trifluoroethyl) thio) phenyl) isoindol-1-one (1 g, 2.6 mmol), 50mL dichloromethane H 2O2 (1.5 g, 30% ag, 13 mmol), acetylacetone (0.27 g, 2.6 mmol) and stannous chloride (0.12 g, 0.53 mmol) were weighed into a 100 mL reaction flask and reacted at 25℃for 24 hours. 50mL dichloromethane was added for dilution, washed sequentially with aqueous sodium thiosulfate and saturated sodium bicarbonate solution, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give 2- (4-chloro-2-fluoro-5- ((2, 2, 2-trifluoroethyl) sulfinyl) phenyl) isoindol-1-one as a white solid 0.96g, with a quantitative hplc content of 98.4% and a corresponding yield of 90.8%.
The nuclear magnetism and mass spectrum data of a part of the compounds and intermediates prepared by the invention are shown in table 2:
TABLE 2
。
According to the preparation method disclosed in the invention, other compounds of the general formula I (compounds I.1 to I.36) and other compounds of the general formula II (compounds II.1 to II.36) shown in the following Table 3 and the following Table 4 can be prepared.
General formula I
TABLE 3 Table 3
General formula II
TABLE 4 Table 4
While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.
Claims (31)
1. A process for preparing a trifluoroethyl sulfide substituted benzene compound represented by the general formula II, comprising the steps of:
Step 1), condensing the compound of the general formula VII with the compound of the general formula VI to obtain a compound of the general formula V;
Step 2), the compound of the general formula V undergoes sulfonation reaction to obtain a compound of the general formula IV;
step 3) the compound of the general formula IV undergoes a reduction reaction to obtain a compound of the general formula III;
step 4) the compound of the general formula III undergoes alkylation reaction to obtain a compound of the general formula II;
wherein:
R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, C 1-C10 alkyl or C 1-C10 haloalkyl;
R 3、R4、R5 and R 6 are each independently selected from hydrogen, halogen, cyano, nitro, C 1-C10 alkyl, C 1-C10 haloalkyl, C 1-C10 alkoxy, or C 1-C10 haloalkoxy;
R 7 is selected from hydrogen, acetyl or G;
in the step 1), a compound of a general formula VII and a compound of a general formula VI are dissolved in a solvent A and react at a temperature of between 0 ℃ and the boiling point of the solvent A to prepare a compound of a general formula V;
In step 2), the compound of the general formula V reacts with a sulfonating reagent at the temperature of-10 ℃ to 200 ℃ to prepare a compound of the general formula IV;
in step 3), the compound of the general formula IV reacts with a reducing agent at a temperature of 0 ℃ to 200 ℃ to prepare a compound of the general formula III;
In the step 4), the compound of the general formula III reacts with a halogenated reagent or sulfonate and alkali in a solvent B at a temperature of from 0 ℃ to the boiling point temperature of the solvent B to obtain a compound of the general formula II; the halogenated reagent is selected from trifluoroiodoethane; the sulfonate is selected from one or more of methanesulfonic acid 2, 2-trifluoroethyl ester, benzenesulfonic acid 2, 2-trifluoroethyl ester or 2, 2-trifluoro-p-toluenesulfonic acid ethyl ester; the base is selected from one or more of trimethylamine, triethylamine, pyridine, DBU, N-diisopropylethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide.
2. The method of claim 1, wherein R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, C 1-C6 alkyl, or C 1-C6 haloalkyl;
And/or R 3、R4、R5 and R 6 are each independently selected from hydrogen, halogen, cyano, nitro, C 1-C6 alkyl, C 1-C6 haloalkyl, C 1-C6 alkoxy, or C 1-C6 haloalkoxy.
3. The method of claim 1, wherein R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, C 1-C4 alkyl, or C 1-C4 haloalkyl;
and/or R 3、R4、R5 and R 6 are each independently selected from hydrogen, halogen, cyano, nitro, C 1-C4 alkyl, C 1-C4 haloalkyl, C 1-C4 alkoxy, or C 1-C4 haloalkoxy.
4. The method of claim 1, wherein R 1 and R 2 are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, or methyl;
And/or R 3、R4、R5 and R 6 are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
5. The method of claim 1, wherein R 1 is fluoro and R 2 is selected from methyl or chloro;
And/or R 3 and R 6 are hydrogen, R 4 and R 5 are each independently selected from hydrogen or fluorine.
6. A process for preparing a trifluoroethyl sulfoxide substituted benzene compound of the general formula I, comprising the steps of:
Step 1') preparing a compound of formula II according to the process of claim 1;
step 2') subjecting a compound of formula II to an oxidation reaction to obtain a compound of formula I;
Wherein R 1 to R 6 are as defined in claim 1;
In step 2'), the compound of formula II is reacted with an oxidizing agent in a solvent C at a temperature of-10 ℃ to the boiling point of said solvent C to produce the compound of formula I.
7. The method of any one of claims 1-6, wherein R 1、R2、R3、R4、R5、R6 and R 7 are defined as follows:
8. The method according to any one of claims 1 to 6, wherein,
In step 1), the molar ratio of the compound of formula VII to the compound of formula VI is 1:1-3;
And/or in step 2) reacting the compound of formula V with a sulphonating agent at a temperature of from-10 ℃ to 160 ℃ to obtain the compound of formula IV.
9. The process of claim 8, wherein the molar ratio of the compound of formula VII to the compound of formula VI is 1:1-2;
and/or the molar ratio of the compound of formula V to the sulfonation reagent is 1:1-100.
10. The process of claim 8, wherein the molar ratio of the compound of formula VII to the compound of formula VI is 1:1-1.5;
and/or the molar ratio of the compound of formula V to the sulfonation reagent is 1:1-80.
11. The process of claim 8, wherein the molar ratio of the compound of formula VII to the compound of formula VI is from 1:1 to 1.1.
12. The method according to any one of claims 1-6, wherein,
The solvent A is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol dimethyl ether, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, acetonitrile, tetrahydrofuran, dioxane, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide;
and/or the sulfonating agent is selected from one or more of chlorosulfonic acid, concentrated sulfuric acid, fuming sulfuric acid, sulfur trioxide and sulfur monochloride.
13. The method according to any one of claims 1 to 6, wherein,
In step 3), reacting the compound of formula IV with a reducing agent at a temperature of 0 ℃ to 150 ℃ to produce a compound of formula III;
And/or in step 4), the molar ratio of the compound of formula III to the addition of the halogenated reagent or sulfonate, base is 1:1-5:1-5.
14. The method of claim 13, wherein,
In step 3), reacting the compound of formula IV with a reducing agent at a temperature of 0 ℃ to 130 ℃ to produce a compound of formula III;
And/or in step 4), the molar ratio of the compound of formula III to the addition of the halogenated reagent or sulfonate, base is 1:1-4:1-4.
15. The method of claim 13, wherein,
In step 3), reacting the compound of formula IV with a reducing agent at a temperature of 0 ℃ to 120 ℃ to produce a compound of formula III;
and/or in step 4), the molar ratio of the compound of formula III to the addition of the halogenated reagent or sulfonate, base is 1:1-4:1-3.
16. The method of claim 13, wherein,
In step 3), the reducing agent consists of a transition metal and an acid, the acid is selected from organic or inorganic acids, and the molar ratio of the compound of the general formula IV to the addition of the transition metal, the acid is 1:1-50:1-100;
And/or in step 4), the molar ratio of the compound of formula III to the addition of the halogenated reagent or sulfonate, base is 1:1-3:1-2.
17. The method of claim 16, wherein,
In step 3), the molar ratio of the compound of formula IV to the transition metal and the acid is 1:1-30:1-100.
18. The method of claim 16, wherein,
In step 3), the molar ratio of the compound of formula IV to the transition metal and the acid is 1:1-20:1-80.
19. The method of claim 16, wherein,
In step 3), the molar ratio of the compound of formula IV to the transition metal and the acid is 1:5-15:5-60.
20. The process according to claim 6, wherein in step 2'), the molar ratio of the compound of formula II to the addition of the oxidizing agent is from 1:1 to 10.
21. The process according to claim 6, wherein in step 2'), the molar ratio of the compound of formula II to the addition of the oxidizing agent is from 1:1 to 8.
22. The process according to claim 6, wherein in step 2'), the molar ratio of the compound of formula II to the addition of the oxidizing agent is from 1:1 to 6.
23. The process according to claim 6, wherein in step 2'), the molar ratio of the compound of formula II to the addition of the oxidizing agent is from 1:1 to 5.
24. The method of claim 16, wherein,
The transition metal is selected from zinc, iron, copper or nickel or a mixture of zinc, iron, copper and nickel mixed in any proportion, and the acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and nitric acid.
25. The process of any of claims 1-6, wherein the solvent B is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diglyme, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, water, acetonitrile, tetrahydrofuran, dioxane, N-dimethylformamide, N-methylpyrrolidone, or dimethyl sulfoxide.
26. The method of claim 6, wherein the oxidizing agent is selected from one or more of m-chloroperoxybenzoic acid, hydrogen peroxide, or sodium periodate;
And/or the solvent C is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diglyme, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, water, acetonitrile, tetrahydrofuran, dioxane, N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.
27. The method according to any one of claims 1-6, wherein,
In the reaction of step 3), red phosphorus and iodine are also added.
28. The process of claim 27, wherein the molar ratio of the compound of formula IV to red phosphorus, iodine is 1:1-10:0.02-0.2.
29. The process of claim 27, wherein the molar ratio of the compound of formula IV to red phosphorus, iodine is 1:2-8:0.05-0.15.
30. The process of claim 27, wherein the molar ratio of the compound of formula IV to red phosphorus, iodine is 1:2-6:0.05-0.1.
31. A compound having a structure represented by formula III:
wherein:
R 1 to R 7 are as defined in any one of claims 1 to 6.
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